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Diabetes 53:376-383, 2004
© 2004 by the American Diabetes Association, Inc.

Mixed Hematopoietic Chimerism Allows Cure of Autoimmune Diabetes Through Allogeneic Tolerance and Reversal of Autoimmunity

Boris Nikolic1, Yasuo Takeuchi2, Igor Leykin2, Yasuhiro Fudaba2, R. Neal Smith3, and Megan Sykes2

1 Renal Unit, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts
2 Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts
3 Department of Pathology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts

Bone marrow transplantation from diabetes-resistant strains with complete replacement of the recipient immune system by the allogeneic donor has led to tolerance to donor islets and cure of diabetes in a mouse model of type 1 diabetes. However, the ability to tolerize host T-cells of diabetic NOD mice is unknown. We demonstrate that nonmyeloablative conditioning achieves mixed hematopoietic chimerism across major histocompatibility complex (MHC) barriers in spontaneously diabetic NOD mice. This conditioning preserves alloreactive and autoreactive diabetogenic host NOD T-cells, but when mixed chimerism was established, diabetic NOD mice accepted donor-type allogeneic islet grafts and were cured of diabetes, despite a significant recipient T-cell contribution. Furthermore, induction of mixed chimerism permitted acceptance of NOD islet grafts, demonstrating reversal of autoimmunity. Allogeneic bone marrow transplantation was critical for tolerization of diabetogenic and alloreactive host T-cells. Thus, mixed hematopoietic chimerism induces tolerance to donor islets and reverses established autoimmunity in diabetic NOD mice.

Address correspondence and reprint requests to Megan Sykes, M.D., Transplantation Biology Research Center, Bone Marrow Transplantation Section, Massachusetts General Hospital, MGH East, Building 149-5102, 13th St., Boston, MA 02129. E-mail: megan.sykes{at}tbrc.mgh.harvard.edu


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Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2004 by the American Diabetes Association.